2019 NPB-11

This case was originally published in 2019. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

A 52-year-old man presented with profound, persistent lower back pain. MRI revealed multiple osseous, paraspinal, and epidural lesions in the thoracic spine causing cord compression (Image A). A brain MRI also revealed multiple, heterogeneously-enhancing masses in the right occipital lobe, parietal lobe, and posterior fossa epidural space (up to 3.7 cm in greatest dimension). Family history was significant for a brother who had a carotid body tumor. The patient underwent surgery for resection and debulking of the occipital mass.

Tissue Site
Right occipital lobe, brain

The whole slide image provided is an H&E-stained image of the occipital lobe of the brain from a resection.

The diagnosis is metastatic paraganglioma (SDHB-deficient), a neural-crest derived tumor of paraganglion cells.

Extra-adrenal paragangliomas arise from either the sympathetic or parasympathetic paraganglia. Parasympathetic paragangliomas are primarily localized to the head and neck ganglia, with further designation based on site of origin (ie, carotid body, jugulotympanicum, vagus nerve, larynx). Sympathetic paragangliomas are localized along vertebra within the abdomen and pelvis. While parasympathetic (head and neck) paragangliomas are rarely functional, sympathetic paragangliomas usually exhibit elevated norepinephrine, or norepinephrine and dopamine.

To date, at least 30% of pheochromocytomas/paragangliomas harbor germline mutations, and at least 20 genes have been implicated in the pathogenesis of both hereditary and sporadic pheochromocytomas/paragangliomas. These mutations have led to suggested classifications using biochemical pathways and genomic-based clusters: pseudohypoxic, abnormal activation of kinase signaling, and Wnt signaling. Mutations involving the succinate dehydrogenase (SDH) gene family are the most common hereditary alterations in pheochromocytomas and paragangliomas. The SDH complex includes several proteins (SDHA, SDHB, SDHC, SDHD); of these, paragangliomas with SDHB mutations have the highest risk of metastasis (30% to 70%) and are predominately seen in sympathetic paragangliomas. Normally the four SDH proteins form a tetramer, and if any of them is mutated, instability of the complex leads to degradation of the SDHB protein. IHC for SDHB thus can be used as a surrogate marker for mutation in any of these genes.

Head and neck parasympathetic paragangliomas (HNPGLs) comprise 20% of extra-adrenal paragangliomas, with the carotid body and laryngeal tumors being most common and least common, respectively. Average patient age at diagnosis is in the fifth decade, and there is a female predominance (8:1) for parasympathetic paragangliomas. Chronic hypoxia arising from high altitude is an additional risk factor for HNPGLs. Surgery is first line treatment for HNPGLs. A shorter survival is seen in patients with distant metastasis and older age (>50 years). The most common mutation seen in HNPGL is in the SDHD gene (80% of cases), and HNPGLs that carry SDHB mutations have the highest rate of metastasis. The majority of sympathetic paragangliomas arise below the diaphragm, but can occur in the thorax and heart. In the most recent iteration of the WHO Classification of Tumours of Endocrine Organs (2017), "malignant" designation was removed and replaced with "metastatic pheochromocytoma/paraganglioma." Benign designation was eliminated to reflect that all pheochromocytomas/paragangliomas have metastatic potential. Lymph nodes, bone, liver, and lung are the most common sites of metastases for sympathetic paragangliomas. A noradrenergic and dopaminergic phenotype, older age at diagnosis, and larger size contribute to metastatic potential. Clinical symptoms can arise from catecholamine production and include hypertension, headaches, tachycardia, and sweating.

Radiographic features of paragangliomas are largely dependent on the anatomical site of origin. Extra-adrenal paragangliomas often exhibit homogeneous or heterogeneous enhancing masses on CT. Paragangliomas can undergo hemorrhage and demonstrate corresponding fluid-fluid levels or focal areas of high attenuation on CT. On MR, they show multiple areas of signal void with foci of hyperintense signal ("salt and pepper"). Angiography will show enlarged feeding arteries and a tumor blush.

Macroscopically, paragangliomas are firm in consistency and usually well circumscribed. Carotid body paragangliomas can surround and encase the carotid artery. Microscopically, HNPGLs and sympathetic paragangliomas exhibit an organoid or "Zellballen" architecture, consisting of small nests of cells that are surrounded by a delicate vascular network (Image B and Image C). These nests are comprised of chief cells, which contain abundant pale cytoplasm, and are surrounded by a single layer of slender spindle-shaped, sustentacular cells. Sympathetic paragangliomas can exhibit irregular-sized nests and form perivascular pseudorosettes. HNPGLs show smaller cells and tend to be higher in cellularity compared to sympathetic paragangliomas. Multiple morphologic variants have also been described including trabecular, spindled, angioma-like, and sclerosing. Sympathetic paragangliomas of the urinary bladder can appear similar to urothelial carcinoma. Useful IHC stains that are positive in paragangliomas include neuroendocrine markers (chromogranin A, synaptophysin, CD56) which identify chief cells (Image D). Chief cells are often negative for cytokeratin (Image E), CEA, and calcitonin. However, chief cells in tumors arising in the filum terminale and cauda equina are often positive for cytokeratin. HNPGLs can be negative for chromogranin A or express a dot-like (Golgi) pattern in contrast to sympathetic paragangliomas. S100 highlights sustentacular cells at the periphery of the nests. The MIB1/Ki67 proliferation is usually less than 1% in both HNPGLs and sympathetic paragangliomas. Loss of SDHB immunoreactivity may be associated with a higher risk of metastasis and, if found, may warrant germline mutation testing, as occult mutations are present in a subset of patients who present with sporadic pheochromocytoma/paragangliomas (Image F and Image G). Tyrosine hydroxylase can be used to determine if the paraganglioma produces catecholamines.

• Extraadrenal paragangliomas are subcategorized into:
• Parasympathetic paragangliomas (head and neck; HNPGLs)
• Sympathetic paragangliomas
• In the most recent iteration of the WHO Classification of Tumours of Endocrine Organs (2017), "malignant" designation was removed and replaced with "metastatic pheochromocytoma/paraganglioma." Benign designation was eliminated.
• Succinate dehydrogenase (SDH) mutations are useful to determine metastatic potential and familial associations.
• At least 30% of pheochromocytomas/paragangliomas are hereditary.

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